Project Summary. It is estimated that by 2050 the number of US citizens over the age of 65 will reach nearly 100 million, more than twice as many as today. As the demographics of the modern world continue to skew older, understanding and mitigating the aging process has become increasingly important within biomedical research. Aging researchers have made many discoveries in the past 25 years and have demonstrated that slowing aging can prevent or delay the formation of many diseases and improve overall health. Many of these conserved ?longevity pathways? were initially discovered using the nematode Caenorhabditis elegans, where easy genetic manipulation and brief lifespans benefit aging research. A number of these highly regarded publications have identified multiple genetic pathways that link the perception of stress by the nervous system with distinct signaling networks and downstream effectors that improve health and longevity. While these studies provide substantial evidence that cell to cell signaling regulates aging and is common to multiple longevity pathways, they lack the specific signals, receptors, neural circuits, and downstream effectors involved. Some of these studies have reported the important neurotransmitter serotonin as a necessary signaling molecule upstream of the metabolic changes that occur in peripheral tissues, which corroborates the preliminary data I will present in this proposal. More specifically, our data show that the most well-studied longevity intervention, dietary restriction (DR), acts in part through a cell non-autonomous signaling pathway that is inhibited by the smell of food in C. elegans. We further find that DR leads to induction of an intestinal gene, flavin-containing monooxygenase-2 (fmo-2), that is both necessary and sufficient to improve healthspan, stress resistance, and longevity. We also observe that induction of fmo-2 and extension of lifespan both depend on the serotonergic signaling and can be recapitulated by the serotonin antagonist drug, mianserin. This project will elucidate components of the cell non-autonomous pathway initiated by the lack of food that eventually leads to intestinal fmo-2 induction and extension of lifespan. To that end I will identify the serotonergic neuron which initiates the signaling cascade (Aim 1), and determine which neuron receives that signal (Aim 2). From here, I will discover the signaling events that occur downstream of serotonin release (or absence) using a number of screening methods (Aim 3). Collectively, these aims will enhance our understandings of a highly conserved signaling pathway that modifies aging. The ultimate goal of my research is to exploit the biological insights gained here to develop therapeutics that increase human healthspan.